基于3,5-双（三氟甲基）苄基L-芳基甘氨酰胺的强效CCR2拮抗剂的发现。
Discovery of 3,5-bis(trifluoromethyl)benzyl L-arylglycinamide based potent CCR2 antagonists.
作者信息
Yang Lihu, Zhou Changyou, Guo Liangqin, Morriello Gregori, Butora Gabor, Pasternak Alexander, Parsons William H, Mills Sander G, MacCoss Malcolm, Vicario Pasquale P, Zweerink Hans, Ayala Julia M, Goyal Shefali, Hanlon William A, Cascieri Margaret A, Springer Marty S
机构信息
Merck Research Laboratories, Rahway, NJ 07065-0900, USA.
出版信息
Bioorg Med Chem Lett. 2006 Jul 15;16(14):3735-9. doi: 10.1016/j.bmcl.2006.04.045. Epub 2006 May 15.
Systematic modification of a screening lead yielded a class of potent glycinamide based CCR2 antagonists. The best compound (55, (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-{[2-(1-piperidinyl)ethyl]amino}-2-(3-thienyl)acetamide) displayed good binding affinity (IC50=30 and 39 nM) toward human monocytes and CHO cell expressing human CCR2b, respectively. Functionally, it blocked MCP-1 (CCL2)-induced calcium mobilization (IC50=50 nM) and chemotaxis mediated through the CCR2 receptor (9.6 nM). It is selective against other chemokine receptors tested.
对一种筛选先导化合物进行系统修饰，得到了一类基于甘氨酰胺的强效CCR2拮抗剂。最佳化合物（55，(2S)-N-[3,5-双（三氟甲基）苄基]-2-{[2-(1-哌啶基)乙基]氨基}-2-(3-噻吩基)乙酰胺）分别对人单核细胞和表达人CCR2b的CHO细胞表现出良好的结合亲和力（IC50 = 30和39 nM）。在功能上，它阻断了MCP-1（CCL2）诱导的钙动员（IC50 = 50 nM）以及通过CCR2受体介导的趋化作用（9.6 nM）。它对所测试的其他趋化因子受体具有选择性。
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